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p38α MAPK is required for tooth morphogenesis and enamel secretion

 Matthew B. Greenblatt  ;  Jung-Min Kim  ;  Hwanhee Oh  ;  Kwang Hwan Park  ;  Min-Kyung Choo  ;  Yasuyo Sano  ;  Coralee E. Tye  ;  Ziedonis Skobe  ;  Roger J. Davis  ;  Jin Mo Park  ;  Marianna Bei  ;  Laurie H. Glimcher  ;  Jae-Hyuck Shim 
 Journal of Biological Chemistry, Vol.290(1) : 284-295, 2015 
Journal Title
 Journal of Biological Chemistry 
Issue Date
Ameloblasts/cytology ; Ameloblasts/metabolism* ; Amelogenin/genetics ; Amelogenin/metabolism ; Animals ; Bone Morphogenetic Protein 2/genetics ; Bone Morphogenetic Protein 2/metabolism ; Bone Morphogenetic Protein 7/genetics ; Bone Morphogenetic Protein 7/metabolism ; Cell Differentiation ; Cell Proliferation ; Dental Enamel/cytology ; Dental Enamel/growth & development ; Dental Enamel/metabolism* ; Gene Expression Regulation, Developmental* ; Incisor/cytology ; Incisor/growth & development ; Incisor/metabolism* ; Integrin beta4/genetics ; Integrin beta4/metabolism ; MAP Kinase Kinase 3/genetics ; MAP Kinase Kinase 3/metabolism ; MAP Kinase Kinase 6/genetics ; MAP Kinase Kinase 6/metabolism ; Mice ; Mice, Transgenic ; Mitogen-Activated Protein Kinase 14/genetics ; Mitogen-Activated Protein Kinase 14/metabolism* ; Odontogenesis/genetics* ; Signal Transduction ; Tissue Culture Techniques ; p21-Activated Kinases/genetics ; p21-Activated Kinases/metabolism
Ameloblast ; Bone Morphogenetic Protein (BMP) ; Ectodermal Dysplasia ; Microtubule-associated Protein (MAP) ; SMAD Transcription Factor ; Tooth Development ; p38 MAPK
An improved understanding of the molecular pathways that drive tooth morphogenesis and enamel secretion is needed to generate teeth from organ cultures for therapeutic implantation or to determine the pathogenesis of primary disorders of dentition (Abdollah, S., Macias-Silva, M., Tsukazaki, T., Hayashi, H., Attisano, L., and Wrana, J. L. (1997) J. Biol. Chem. 272, 27678-27685). Here we present a novel ectodermal dysplasia phenotype associated with conditional deletion of p38α MAPK in ectodermal appendages using K14-cre mice (p38α(K14) mice). These mice display impaired patterning of dental cusps and a profound defect in the production and biomechanical strength of dental enamel because of defects in ameloblast differentiation and activity. In the absence of p38α, expression of amelogenin and β4-integrin in ameloblasts and p21 in the enamel knot was significantly reduced. Mice lacking the MAP2K MKK6, but not mice lacking MAP2K MKK3, also show the enamel defects, implying that MKK6 functions as an upstream kinase of p38α in ectodermal appendages. Lastly, stimulation with BMP2/7 in both explant culture and an ameloblast cell line confirm that p38α functions downstream of BMPs in this context. Thus, BMP-induced activation of the p38α MAPK pathway is critical for the morphogenesis of tooth cusps and the secretion of dental enamel.
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Yonsei Authors
Park, Kwang Hwan(박광환) ORCID logo https://orcid.org/0000-0002-2110-0559
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